Background: Growing evidence shows that impaired signaling of Insulin-like Growth Factor-1 (IGF-1) is associated with neurodegenerative disorders, such as Parkinson's disease (PD). However, there is still controversy regarding its proinflammatory or neuroprotective function. In an attempt to elucidate the contribution of IGF-1 in PD, we aimed to discover the relation between serum IGF-1 levels in drug-naïve early PD patients and cerebrospinal fluid (CSF) biomarkers as well as microstructural changes in brain white matter. Methods: The association between quartiles of serum IGF-1 levels and CSF biomarkers (α-synuclein, dopamine, amyloid-β1-42, total tau, and phosphorylated tau) was investigated using adjusted regression models in 404 drug-naïve early PD patients with only mild motor manifestations and 188 age- and sex-matched healthy controls (HC) enrolled in the Parkinson's Progression Markers Initiative (PPMI). By using region of interest analysis and connectometry approach, we tracked the white matter microstructural integrity and diffusivity patterns in a subgroup of study participants with available diffusion MRI data to investigate the association between subcomponents of neural pathways with serum IGF-1 levels. Results: PD patients had higher levels of IGF-1 compared to HC, although not statistically significant (mean difference: 3.60, P = 0.44). However, after adjustment for possible confounders and correction for False Discovery Rate (FDR), IGF-1 was negatively correlated with CSF α-synuclein, total and phosphorylated tau levels only in PD subjects. The imaging analysis proved a significant negative correlation (FDR corrected P-value = 0.013) between continuous levels of serum IGF-1 in patients with PD and the connectivity, but not integrity, in following fibers while controlling for age, sex, body mass index, depressive symptoms, education years, cognitive status and disease duration: middle cerebellar peduncle, cingulum, genu and splenium of the corpus callosum. No significant association was found between brain white matter microstructral measures or CSF markers of healthy controls and levels of IGF-1. Conclusion: Altered connectivity in specific white matter structures, mainly involved in cognitive and motor deterioration, in association with higher serum IGF-1 levels might propose IGF-1 as a potential associate of worse outcome in response to higher burden of α-synucleinopathy and tauopathy in PD.